ClinVar Genomic variation as it relates to human health

NM_000155.3(GALT):c.292G>C(D98H) is a missense variant classified as likely pathogenic in the context of galactosemia. D98H has been observed in cases with relevant disease (PMID: 21228398, 27308838, 14728988, 31395954). Functional assessments of this variant are not available in the literature. D98H has been observed in population frequency databases (ExAC: OTH 0.11%). In summary, NM_000155.3(GALT):c.292G>C(D98H) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Variant summary: GALT c.292G>C (p.Asp98His) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain (IPR005849) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Moreover, another variant affecting the same residue, p.Asp98Asn has been reported to be associated with galactosemia indicating the variant to be located in a mutational hotspot and the clinical importance of the Asp98 residue. The variant allele was found at a frequency of 4e-06 in 251508 control chromosomes. c.292G>C has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Galactosemia (example, Berry_2004, Reichardt_1991). These data indicate that the variant is very likely to be associated with disease. It was reported in patients with hereditary galactosemia and proven reduced enzyme activity (less than 10% of the WT enzyme) suggesting pathogenicity (unpublished finding). The following publications have been ascertained in the context of this evaluation (PMID: 15172000, 1766867). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The GALT c.292G>C variant is predicted to result in the amino acid substitution p.Asp98His. This variant has been reported along with a second GALT variant in at least two individuals with galactosemia (Berry et al. 2004. PubMed ID: 14728988; Supplemental Table 3b in Wojcik et al. 2019. PubMed ID: 31395954). A different substitution impacting the same amino acid (p.Asp98Asn) has been reported in patients with galactosemia (e.g., Webb et al. 2003. PubMed ID: 12595586; Liu et al. 2012. PubMed ID: 22743281). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-34647528-G-C). In summary, this variant is interpreted as likely pathogenic.

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 98 of the GALT protein (p.Asp98His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with galactosemia (PMID: 14728988, 31395954). ClinVar contains an entry for this variant (Variation ID: 25149). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALT protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Asp98 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10408771, 12595586, 22743281). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.